Mitogen-activated protein kinases (MAPKs) (ERK1/2, JNK, and p38) are upregulated in diabetic cardiomyopathy (DCM). Dual-specific phosphatase-1 (DUSP-1) has been reported to regulate the activity of MAPKs in cardiac hypertrophy; however, the role of DUSP-1 in regulating MAPKs activity in DCM is not known. MicroRNAs have been reported to regulate the expression of several genes in hypertrophied failing hearts. However, little is known about the microRNAs regulating DUSP-1 expression in diabetes-related cardiac hypertrophy. In the present study, we investigated the role of DUSP-1 and miR-200c in diabetes-induced cardiac hypertrophy. DCM was induced in Wistar rats by low-dose Streptozotocin high-fat diet for 12 weeks. Cardiac expression of ERK, p-38, JNK, DUSP-1, miR-200c, and hypertrophy markers (ANP and β-MHC) was studied in DCM in control rats and in high-glucose (HG)-treated rat neonatal cardiomyocytes. miR-200c inhibition was performed to validate DUSP-1 as target. A significant increase in phosphorylated ERK, p38, and JNK was observed in DCM model and in HG-treated cardiomyocytes (p < 0.05). Expression of DUSP-1 was significantly decreased in diabetes group and in HG-treated cardiomyocytes (p < 0.05). Increased expression of miR-200c was observed in DCM model and in HG-treated cardiomyocytes (p < 0.05). Inhibition of miR-200c induces the expression of the DUSP-1 causing decreased expression of phosphorylated ERK, p38, and JNK and attenuated cardiomyocyte hypertrophy in HG-treated cardiomyocytes. miR-200c plays a role in diabetes-associated cardiac hypertrophy by modulating expression of DUSP-1.

SUMMARYAim: Cardiac hypertrophy and myocardial fibrosis significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Altered expression of several genes and their regulation by microRNAs has been reported in hypertrophied failing hearts. This study aims to examine the role of Cdc42, Pak1, and miR-30c in the pathogenesis of cardiac hypertrophy in DCM. Methods: DCM was induced in Wistar rats by low-dose streptozotocin-high-fat diet for 12 weeks. Cardiac expression of Cdc42, Pak1 and miR-30c, and hypertrophy markers (ANP and b-MHC) was studied in DCM vs control rats and in high-glucose (HG)-treated H9c2 cardiomyocytes. Results: Diabetic rats showed cardiomyocyte hypertrophy, increased heart-to-body weight ratio, and an increased expression of ANP and b-MHC. Cardiac expression of Cdc42 and Pak1 genes was increased in diabetic hearts and in HG-treated cardiomyocytes. miR-30c was identified to target Cdc42 and Pak1 genes, and cardiac miR-30c expression was found to be decreased in DCM rats, patients with DCM, and in HG-treated cardiomyocytes. miR-30c overexpression decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas miR-30c inhibition increased Cdc42 and Pak1 gene expression and myocyte hypertrophy in HG-treated cardiomyocytes. Conclusion: Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes.

Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm’s canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer’s vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.

Aims: To test the anaerobic fungus, Piromyces sp. FNG5, for its tolerance to phenolic monomers released in the rumen by degradation of lignocellulosic poor-quality feeds. Methods and Results: Effects of phenolic monomers on biomass and fibrolytic enzyme activities of a pure culture of lignocellulolytic anaerobic fungus (Piromyces sp. FNG5) isolated from faeces of wild nil gai (blue bull, Baselophus tragocamelus) were evaluated. There was a reduction in fungal biomass at 1 mM M concentration of catechol with complete inhibition at 10 mM M. p-Coumaric acid caused a reduction in biomass at 10 mM M and no growth was observed above 20 mM M concentration. The fungal isolate could tolerate up to 5 mM M of ferulic acid without any reduction in biomass level, and was able to grow to some extent up to the highest level of ferulic acid tested (20 mM M). Vanillic acid had no effect on biomass of the fungus even up to 50 mM M level. The phenolic monomers varied in their potential to inhibit the secretion of carboxymethyl cellulase, xylanase, b-glucosidase and acetyl esterase activities with catechol being the most inhibitory and vanillic acid being the least inhibitory. After 14 days of incubation, 38AE49-65AE14% p-Coumaric acid, 65AE22-74AE10% ferulic acid and 34AE13-66AE78% vanillic acid disappeared from the medium under anaerobic conditions. Conclusions, Significance and Impact of the Study: It is concluded that the anaerobic fungus Piromyces sp. FNG5 is tolerant to phenolic monomers and has ability to degrade them. Therefore, such anaerobic fungi may play an important role in fibre degradation in the rumen.

The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanotechnology. Thus, rising production of nanoparticles (NPs) increases the possible risks to the environment and occupationally exposed humans. Hence, it is indispensable to appraise the safety toxicity including genotoxicity for these NPs. In the present study, we have evaluated the genotoxic effect of ZnO NPs after oral administration to Swiss mice at dose levels of 300 and 2000 mg/kg body weight. These doses were administered for 2 days at 24 h apart. Chromosomal aberration (CA) and micronucleus tests were conducted following Organization for Economic Co-operation and Development guidelines. DNA damage was evaluated at 0, 24, 48, and 72 h posttreatment using a randomly amplified polymorphic DNA (RAPD) assay; additionally, semen analyses were also performed at 34.5 days post oral exposure. The reactive oxygen species (ROS), 8-oxo-2'-deoxyguanosine and CAs were increased ( p < 0.05) at the highest dosage (2000 mg/kg) of ZnO NPs compared to controls. Aberrant sperm morphology with reduced sperm count and motility were also present ( p < 0.05) in the high-dose group. Based on the RAPD assay, the genomic template stability within the high-dose group (<90%) was less than the controls (100%). The results suggested that ZnO NPs are mildly genotoxic in a dose-related manner and this toxicity were induced by generation of ROS.

The purpose of this study was to learn the skin dose estimation for various beam modifiers at various source-to-surface distances (SSDs) for a 6 MV photon. Surface and buildup region doses were measured with an acrylic slab phantom and Markus 0.055 cc parallel plate (PP) ionization chamber. Measurements were carried out for open fields, motorized wedge fields, acrylic block tray fields ranging from 3 × 3 cm2 to 30 × 30 cm2. Twenty-five percent of the field was blocked with a cerrobend block and a Multileaf collimator (MLC). The effect of the blocks on the skin dose was measured for a 20 × 20 cm2 field size, at 80 cm, 100 cm and 120 cm SSD. During the use of isocentric treatments, whereby the tumor is positioned at 100 cm from the source, depending on the depth of the tumor and size of the patient, the SSD can vary from 80 cm to 100 cm. To achieve a larger field size, the SSD can also be extended up to 120 cm at times. The skin dose increased as field size increased. The skin dose for the open 10 ×10 cm2 field was 15.5%, 14.8% and 15.5% at 80 cm, 100 cm and 120 cm SSDs, respectively. The skin dose due to a motorized 60° wedge for the 10 × 10 cm2 field was 9.9%, 9.5%, and 9.5% at 80 cm, 100 cm and 120 cm SSDs. The skin dose due to acrylic block tray, of thickness 1.0 cm for a 10 × 10 cm2 field was 27.0%, 17.2% and 16.1% at 80, 100 and 120 cm SSD respectively. Due to the use of an acrylic block tray, the surface dose was increased for all field sizes at the above three SSDs and the percentage skin dose was more dominant at the lower SSD and larger field size. The skin dose for a 30 × 30 cm2 field size at 80 cm SSD was 38.3% and it was 70.4% for the open and acrylic block tray fields, respectively. The skin doses for motorized wedge fields were lower than for open fields. The effect of SSDs on the surface dose for motorized 60° wedge fields was not significant for a small field size (difference was less than 1% up to a 15 × 15 cm2 field size), but for a larger field (field size more than 15 × 15 cm2), the difference in a percentage skin dose was significant. The skin dose for the open field was more than that for the MLC blocked field and lower than that for the acrylic blocked tray field. The block was 25% of the 20 × 20 cm2 open field. Skin doses were increased as the SSD decreased and were dominant for larger field sizes. The surface dose was weakly dependent on the MLC block.

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